Potassium is the most abundant intracelluar cation, and is very important in maintaining physiological homeostasis. Potassium channels are present in almost all vertebrate cells, and the potassium influx through these channels is indispensable for maintaining hyperpolarized resting membrane potential.
Large conductance calcium activated potassium channels (also referred to as BK channels or maxi-K channels) are expressed especially in neurons and smooth muscle cells. Because both of the increase of intracellular calcium concentration and membrane depolarization can activate maxi-K channels, maxi-K channels have been thought to play a pivotal role in regulating voltage-dependent calcium influx. Increase in the intracellular calcium concentration mediates many processes such as release of neurotransmitters, contraction of smooth muscles, cell growth and death, and the like. Actually, the opening of maxi-K channels causes strong membrane hyperpolarization, and inhibits these calcium-induced responses thereby. Accordingly, by inhibiting various depolarization-mediated physiological responses, a substance having an activity of opening maxi-K channels is useful for the treatment of diseases such as cerebral infarction, subarachnoid hemorrhage, pollakiuria, urinary incontinence, and the like.
There has been a report that a medicine which opens BK channels has activities to inhibit electrically induced contraction of respiratory tract preparation of guinea pig (nonpatent document 1). Therefore, it is effective for treatment of, for example, asthma, COPD, etc. Also, there has been suggested that a medicine which opens BK channels can be an agent for treatment of sexual function disorder such as erectile dysfunction, etc. (patent document 1).
There have been various reports on large conductance calcium-activated potassium channel openers. For example, pyrrole derivatives (patent document furan derivatives (patent document 3), nitrogen-containing 5-membered ring derivatives in which the nitrogen atom is substituted by phenyl or benzyl (patent document 4), diphenyltriazole derivatives (nonpatent document 2), Celecoxib derivative, etc. (patent document 5), diphenylheterocyclic compounds (patent document 6), nitrogen-containing 5-membered heterocyclic ring compounds (patent document 7), imidazole compounds (patent document 8), thiazole compounds (patent document 9) etc.
There has been a report on a method of treating neuromuscular dysfunction of the lower urinary tract in mammal comprising administrating a cyclooxygenase inhibitor (patent document 10) and a report on a method of treating pollakiuria comprising administrating Niflumic acid known as cyclooxygenase inhibitor (nonpatent document 3). However, there have also been various reports on side effects caused by inhibiting cyclooxygenases, known as COX-1 and COX-2. The primary side effects associated with the administration of Nonsteroidal anti-inflammatory drugs (“NSAIDs”), whose primary pharmacological action is the inhibition of both COX-1 and COX-2, are gastrointestinal upset and injury. It is generally understood that these effects are primarily due to the inhibition of protective prostaglandins produced through the COX-1 pathway. As regards side effects associated with COX-2 inhibitors, there have been reported for increased incidence of cardiovascular events (nonpatent documents 4 to 6, etc).
There have been various reports on pyrimidine, pyridine and triadine derivatives. For example, pyrimidine derivatives (patent documents 11, 12, and 13), triadine derivatives (nonpatent document 7), etc.    [patent document 1] WO 00/34244    [patent document 2] WO 96/40634    [patent document 3] JP 2000-351773    [patent document 4] WO 98/04135    [patent document 5] EP 1400243    [patent document 6] JP 2000-516925    [patent document 7] WO 02/83111    [patent document 8] WO 2006/030977    [patent document 9] WO 2007/51133    [patent document 10] U.S. Pat. No. 6,440,963    [patent document 11] WO 2006034473    [patent document 12] WO 2004011442    [patent document 13] WO 2006084017    [nonpatent document 1] J. Pharmacol. Exp. Ther., (1998) 286: 952-958    [nonpatent document 2] J. Med. Chem., Vol. 45, p. 2942-2952 (2002)    [nonpatent document 3] Therapy, 1970, XXV, 1051    [nonpatent document 4] N. Engl. J. Med., 352, 1071 (2005)    [nonpatent document 5] N. Engl. J. Med., 352, 1081 (2005)    [nonpatent document 6] N. Engl. J. Med., 352, 1092 (2005)    [nonpatent document 7] Zhurnal Obshchei Khimii (1972), 42(10), 2280